Leukotriene biosynthesis inhibitors

ABSTRACT

Various substituted benzoxazoles and benzothiazoles, are described and disclosed, which are potent inhibitors of leukotriene synthesis in warm-blooded animals.

This is a continuation of application Ser. No. 08/168,591, filed Dec. 16, 1993, abandoned, which is a division of application Ser. No. 07/937,315, filed Sep. 4, 1992, now U.S. Pat. No. 5,296,486, which is a continuation of application Ser. No. 07/764,591, filed Sep. 24, 1991, abandoned.

Leukotrienes (LTs) are potent, pro-inflammatory substances that are produced in the metabolism of arachidonic acid. It is believed that LTs play a role in various inflammatory diseases, such as asthma, allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease and psoriasis. Accordingly, inhibition of the biosynthesis of LTs has potential utility in the treatment of diseases in which inflammation and arachidonic acid metabolism have been implicated.

The biosynthesis of leukotrienes and their pathophysiology have been well documented. Many investigators have been seeking to block the pathophysiological effects of leukotrienes either by blocking their biosynthesis or by blocking their activity at the receptor level. Two recent reviews (J. H. Musser and A. F. Kreft, J. Med. Chem. 1992, 35,2501 and A. Shaw and R. D. Krell, J. Med. Chem. 1991, 34, 1235) describe the status of research in these areas, including results of clinical trials. Results of clinical trials such as those cited in these articles support the concept that agents that block the biosynthesis or activity of leukotrienes will be useful in asthma and possibly other inflammatory diseases mentioned above.

This invention relates to various substituted benzoxazoles, benzothiazoles, oxazolopyridines and thiazolopyridines which have the ability to inhibit leukotriene biosynthesis. Such compounds have the general formula: ##STR1## wherein X is O or S;

Y is C or N;

Z is C or N;

with the proviso that Y and Z are not both N;

R₁ and R₂ are each, independent of one another, hydrogen; C₁ -C₆ alkyl; halo; CF₃ ; nitrile; C₁ -C₆ alkoxy; --CO₂ R₇ wherein R₇ is hydrogen or C₁ -C₆ alkyl; --C(O)NR₈ R₉ wherein R₈ and R₉ are hydrogen, C₁ -C₃ alkyl, methoxy or together with N form a morpholine, pyrrolidine or piperidine ring; --NO₂ ; --NR₁₀ R₁₁ wherein R₁₀ and R₁₁ are hydrogen or C₁ -C₆ alkyl; --C(O)R₁₂ wherein R₁₂ is C₁ -C₆ alkyl; --SO₂ R₁₂ ; --NHC(O)R₁₂ ; --NHSO₂ R₁₂ ; or --SO₂ NR₁₃ R₁₄ wherein R₁₃ and R₁₄ are hydrogen or C₁ -C₆ alkyl

R₃ is cyclohexyl or an unsubstituted or substituted phenyl ring wherein the substituents are selected from halo, CF₃, C₁ -C₄ alkyl and C₁ -C₄ alkoxy; SO₂ R₁₂ ; --NHC(O)R₁₂, --NHSO₂ R₁₂ ; --SO₂ NR₁₃ R₁₄ or NO₂ ; or R₃ may be a 1-piperidinyl ring, a 2-, 3- or 4- pyridine ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, an imidazole ring optionally substituted on nitrogen with C₁ -C₄ alkyl, or a 2-thiazole ring or a 2-methyl-4-thiazole ring; R₃ may also be a dialkylamine (C₁ -C₄) or an alkyl ether (C₁ -C₄).

R₄ is an ester of structure --CO₂ R₁₆ wherein R₁₆ is C₁ -C₄ alkyl; or an amide of structure --C(O)NR₁₇ R₁₈ wherein R₁₇ and R₁₈ are hydrogen, C₁ -C₃ alkyl, methoxy or together with N form a morpholine ring, or together with N form a piperidine or pyrrolidine ring; an unsubstituted or substituted phenyl ring wherein the substituents are selected from halo, C₁ -C₄ alkyl or C₁ -C₄ alkoxy; a 3-methyl-1,2,4-oxadiazol-5-yl group; a 2- or 3-thienyl group; or a 2-, 3-, or 4-pyridyl group; a 2-imidazole group optionally substituted on N with a methyl group; a 2-thiazole group optionally substituted on the 4-position with a methyl; a ketone of structure C(O)R₁₉ wherein R₁₉ is C₁ -C₃ alkyl, phenyl or 1-methylimidazol-2-yl; an ether --CH₂ OR₂₀ where R₂₀ =C₁ -C₃ alkyl, a thioether, --CH₂ SR₂₀ ; a sulfone, --CH₂ SO₂ CH₃ ; an amine, --CH₂ N(R₂₀)₂ ; an amine derivative, --CH₂ NHC(O)R₂₁, where R₂₁ is CH₃ or NHCH₃, or --CH₂ NHSO₂ Me₂ ; or a carbamate, --CH₂ OC(O)NHMe;

R₅ and R₆ are independently of each other hydrogen or methyl; and

n is an integer 0, 1 or 2.

Such compounds may be in racemic form, or the pure or substantially pure enantiomers may be isolated. The preferred compounds are those wherein the R₁ substituent is in the 5-position and is an C₁ -C₃ alkyl group or halogen, the R₃ substituent is cyclohexyl, the R₆ substituent is hydrogen and n is 1.

In J. Pharm. Sci (57, p. 1695) by S. Advani and J. Sam (1968) four compounds are disclosed having a basic structure like that of Formula I. The Advani publication, a publication on potential anti-neoplastic agents, discloses synthesis of these four compounds, but no biological activity is provided. In the Advani publication, Y and Z are both carbon, R₄ is --CO₂ C₂ H₅, R₁ and R₂ are both hydrogen and R₃ is 4--C₆ H₄ OH, --C₆ H₅, 4 -imidazolyl or --CH₂ SCH₃.

In Ger. Off. DE 3419994 there are described compounds of general formula I wherein both Y and Z are C, X is O or S, R₁ and R₂ are hydrogen, halo, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, CN, NO₂ or CF₃, R₄ is --C(O)OR₁₆, (wherein R₁₆, is hydrogen, alkyl, alkenyl or alkynyl), --C(O)N(R₁₈) (R₁₉) (wherein R₁₈ and R₁₉ are hydrogen, C₁ -C₆ alkyl, phenyl or alkoxy or together with N form a pyrrolidine, piperidine or morpholine ring), --CN or --C(S)NH₂. The group referred to as "Y" in such Ger. Off. DE 3419994 consists of R₃ and the carbon chain, i.e., (CH₂)_(n) shown in Formula I. The groups at "Y" disclosed in such German publication are straight-chain or branched alkyl (C₁ -C₈, with one to three carbons between N and R₄, or the group designated "Z" in such published application, methylthioalkyl (one to three carbons in the alkyl) or phenylalkyl. Specifically not disclosed at R₃ is a cyclohexyl group or substituted phenyl. Also, not disclosed at R₄ are ketones or phenyl and heteroaromatic or heterocyclic rings. Finally, also not disclosed in the German publication is Y or Z being nitrogen. At R₆ the German publication discloses hydrogen and C₁ -C₄ alkyl. Specifically not disclosed are the preferred compounds of the present invention. Compounds disclosed in the German publication are said to be useful for protecting crops against certain classes or types of herbicides.

The compounds of the present invention may be prepared by methods and processes known in the art and published in the literature. For example, compounds may be prepared by reaction of an appropriately substituted 2-chlorobenzoxazole, 2-chlorobenzothiazole, 2-chlorooxazolopyridine or 2-chlorothiazolopyridine with an amine, an amino acid or an amino acid ester. Such synthesis scheme is outlined herein below as Scheme A. ##STR2## The reaction of Scheme A may occur in an inert solvent, such as methylene chloride, toluene or DMSO, with a basic catalyst, such as triethylamine or NaOH. The optimum choice of both solvent and catalyst will depend on the nature of the reactants, as a person skilled in the art would recognize.

Alternatively, modification of a procedure known in the literature for preparation of 2-aminobenzothiazoles may be successfully employed for synthesis of compounds of general formula I. Such synthesis scheme is outlined hereinbelow as Scheme B. ##STR3## The procedure of Scheme B involves reaction of an appropriately substituted isothiocyanate with a amine or an amino acid ester in a suitable inert solvent, such as ether, followed by cyclization of the intermediate thiourea with sulfuryl chloride or bromine in another inert solvent, again such as ether or perhaps chlorobenzene. ##STR4## The synthesis of Scheme C can be employed for those compounds of general formula I wherein X is S and Z is N. A haloaminopyridine is converted to an isothiocyanate, for example by reaction with thiophosgene, in the presence of a base, such as sodium carbonate, in an inert solvent. Treatment of the isothiocyanate with an amine in an inert solvent yields a thiazolopyridine. With certain additional substituents on the 2-chloro-3-aminopyridine ring, an intermediate thiourea is isolated upon reaction with the isothiocyanate. In that case, cyclization to the thiazolopyridine product may be accomplished by heating in an inert solvent with either acid or base catalysis, for example in ethanolic HCl or DMF with K₂ CO₃.

Isomeric thiazolopyridines may be prepared by cyclization of a 3-halo-2-thiourea substituted pyridine. Such a synthetic scheme is outlined hereinbelow as Scheme D. ##STR5## In Scheme D, the 3-halo-2-thiourea pyridine is heated in an inert solvent with base catalysis, for example K₂ CO₃ in DMF. The intermediate 2-amino-3-halopyridine may be prepared, for example, by bromination of an optionally substituted 2-aminopyridine. The isothiocyanate may be prepared as described in Scheme C.

Compounds of general formula I wherein R₄ is an acid or an ester may be modified to yield compounds of general formula I wherein R₄ is an amide, a methyloxadiazole a ketone an ether, or thioether. The scheme for such modification is shown hereinbelow as Scheme E. ##STR6## All the general methods exemplified in Scheme E are well known to one skilled in the art, and are also published in the chemical literature.

Concerning the stereochemistry of compounds produced via the methods and schemes outlined hereinabove, if the starting amines used in Schemes I and II above are enantiomerically pure, then a single enantiomer of the end product, having either R or S configuration at the asymmetric carbon, will be recovered. By the same token, if the starting amine is racemic, that is, a mixture of R and S, then a racemic end product will be recovered. Racemic compounds may be separated into the individual enantiomers by methods known to one skilled in the art, for example, by resolution of a diastereomeric salt, chromatography on a chiral column, etc. In the text of this specification the designation for enantiomers of amino acids D and L, or racemic DL, will be used.

The following examples are illustrative of the present invention. Such examples, however, are not to be construed as limiting the scope of the present invention, which scope is defined in the claims which follow. As would be obvious to one skilled in the art, other compounds, such as where R₄ is pyrrolidine-amide, can be readily synthesized using the methods and procedures outline above.

EXAMPLE 1 DL-N-(Benzothiazol-2-yl)phenylalanine hydrochloride

11.8 g phenylalanine (73.4 mmol) was added in portions to a suspension of 5.7 g powdered NaOH (143 mmol) in 50 mL DMSO, and stirred under nitrogen. 2-Chlorobenzothiazole (11 g, 65 mmol) was added over fifteen minutes at room temperature. The reaction was heated on an oil bath at about 95° C. for 4 hours. The reaction mixture was then cooled, poured into 200 mL ice and water, and the pH of the resulting mixture was adjusted to about 1-2 by addition of 10N HCl.

More ice was added, and the mixture was then stirred and filtered. The white solid was dissolved in alkaline solution, stirred with celite, filtered, acidified with 2N HCl and filtered. The resulting solid was rinsed with water, then EtOH, and dried. The product (6.47 g, 19.3 mmol, 30%) melted at 250°-251° C.

EXAMPLE 2 DL-N-(Benzothiazol-2-yl)phenylalanine ethyl ester

Compound No. 4, Table 1

Thionyl chloride (3.82 g, 32.1 mmOl) was added dropwise to the product from Example 1 (3.2 g, 10.7 mmol) suspended in 200 mL EtOH. The reaction was heated at reflux for four hours. The reaction mixture was then concentrated, the residue dissolved in EtOAc (75mL) and extracted with saturated Na₂ CO_(') solution (2×50 mL), saturated NaCl solution (50 mL) dried (Na₂ SO₄) and concentrated. The product was recrystallized from EtOH giving 2.25 g (6.9 mmol, 64%) mp 137°-139° C.

EXAMPLE 3 DL-N-(6-Isopropylbenzothiazol-2-yl)-4-chlorophenylalanine ethyl ester

Compound No. 7, Table 1

DL-4-Chlorophenylalanine ethyl ester hydrochloride(5g, 18.9 mmol) was converted to the free base using triethylamine. A solution of the free base in 75 mL ether was added to a solution of 4isopropylphenylisothiocyanate in 150 mL ether, cooled on an ice-salt bath. The temperature was maintained at about 0° C. during addition. The reaction was stirred for four and one-half hours, at which time the reaction temperature was 12° C. The reaction mixture was filtered, the filtrate concentrated, and the resulting foamy residue triturated with petroleum ether while cooling on ice. This resulted in 6.1 g (15.1 mmol, 80%) N-(4-isopropylphenyl)-N'-[2-(4-chlorophenyl)-1-(ethoxycarbonyl)ethyl]thiourea, mp 73°-75° C.

The intermediate product (6 g, 14.8 mmol) was dissolved in 25 mL chlorobenzene and cooled on an ice bath to 0° C. Sulfuryl chloride (2.76 g, 20.4 mmol) in 5 mL chlorobenzene was added dropwise. After five and one-half hours, the reaction mixture was concentrated, the residue dissolved in EtOAc (150 mL), washed with saturated Na₂ CO₃ solution, then saturated NaCl solution, dried (Na₂ SO₄) and concentrated. The product crystallized from EtOH, giving 4.07g(10.1 mmol, 68%), mp 105°-107° C.

EXAMPLE 4 2-(2-Cyclohexyl-1-phenyl]ethylaminobenzoxazole

Compound No. 51, Table 3

A mixture of 1.12 g 2-chlorobenzoxazole (7.3 mmol), 1.48 g 2-cyclohexyl-1-phenylethylamine (7.3 mmol) and 0.88 g triethylamine (8.8 mmol) in 305 mL CH₂ Cl₂, was refluxed for 31 hours. The reaction mixture was diluted with 50 mL CH₂ Cl₂, extracted with water (1×50 mL), 1N HCl (1×50 mL), saturated NaCl (1×50 mL), dried (Na₂ SO₄) and concentrated. The resulting solid was recrystallized from EtOH giving 1.4 g product (4.4 mmol, 60%) mp 129°-131° C.

EXAMPLE 5 L-2-[2-Cyclohexyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]amino-5-methylbenzoxazole

Compound No. 125, Table 6

0.47 g 60% NaH in mineral oil dispersion (0.28 g NaH, 11.8 mmol), 0.39 g acetamidoxime (5.3 mmol), 1.48 g N-(5-methylbenzoxazol-2-yl)cyclohexylalanine methyl ester (4.7mmol), and several molecular sieves were combined in 20 mL THF and refluxed for two hours under nitrogen. The mixture was poured into water and extracted with EtOAc. The EtOAc was dried (Na₂ SO₄) and concentrated. The product was purified by flash chromatography on silca gel (99 CH₂ Cl₂ :1 MeOH). After triturating with petroleum ether the product was obtained as a white solid, 70 mg, mp 118°-119° C.

EXAMPLE 6 L-N-(5-Methylbenzoxazol-2-yl)cyclohexylalanine-N'-methylamide

Compound No. 144, Table 2

A solution of 1.08 g L-N-(5-methylbenzoxazol-2-yl)cyclohexylalanine (3.6 mmol) in 15 mL CH₂ Cl₂ was cooled on an ice bath. Carbonyldiimidazole (0.88g, 5.4mmol) was added in portions. After one hour methylamine gas was bubbled into the reaction mixture for about forty-five minutes. The reaction was diluted with CH₂ Cl₂, washed with water, saturated NaCl solution, dried (Na₂ SO₄) and concentrated. The product was purified by flash chromatography on silica gel, eluting with 99 CH₂ Cl₂ :1 MeOH, followed by recrystallization from isopropanol giving 0.2 g product, m.p. 202°-204° C.

EXAMPLE 7 3-[(6-Isopropylbenzothiazol-2-yl)amino]-4-phenylbutan-2-one

Compound No. 128, Table 7

A solution of 2 g N-(6-isopropylbenzothiazol-2-yl)phenylalanine (5.9 mmol) in 60 mL THF was cooled on an ice-salt bath to -5° C., under nitrogen. A solution of 1.4N MeLi in ether (26 mL, 36.4mmol) was added via syringe over about one minute. After two hours 10 mL chlorotrimethylsilane (78 mmol) was added rapidly and the reaction warmed up to room temperature. The reaction was quenched with 1N HCl and the product extracted into ether, dried (Na₂ SO₄) and concentrated. The product was purified by flash chromatography thru silica gel, eluting with CH₂ Cl₂. Recrystallization from EtOH gave 0.75g product (2.2 mmol, 38%), mp 107°-110° C.

EXAMPLE 8 2-[(2-Cyclohexyl-1-phenylethyl)amino]thiazolo[5,4-b]pyridine

Compound No. 171, Table 11

A mixture of 1.28 g (10 mmol) 3-amino-2-chloropyridine, 2.1 g (20 mmol) sodium carbonate and 1.38 g (12 mmol) thiophosgene in 50 mL CH₂ Cl₂ was stirred overnight at room temperature. The reaction mixture was poured into water, and extracted with CH₂ Cl₂. The combined organic extracts were washed with saturated NaCl solution, dried (Na₂ SO₄) and concentrated to give an oil. The product was purified by chromatography on silica gel, eluting with petroleum ether, giving 1.6 g thioisocyanate (9.4 mmol, 94%).

The thioisocyanate (0.516 g, 3.02 mmol) was added to a mixture of 0.66 g 2-cyclohexyl-1-phenylethylamine hydrochloride (2.75 mmol), and 0.278 g triethylamine (2.75 mmol) in 25 mL THF. The reaction was heated at reflux for two hours, poured into water, and extracted with ether. The organic extracts were washed with saturated NaCl solution, dried (MgSO₄) and concentrated. Recrystallization of the residue from CH₂ Cl₂ --petroleum ether gave 0.625 g product (1.84 mmol, 67%) mp 146°-148° C.

EXAMPLE 9 2-{[2-Cyclohexyl-1-(2-pyridyl)ethyl]amino)-6-methylthiazolo-(4,5-b]pyridine

Compound No. 146, Table 11

Bromine (3.19 g) was added dropwise at 0° C. to a solution of amino-5-picoline in 75 mL CH₂ Cl₂. After about two hours at room temperature, the reaction was extracted with saturated sodium carbonate solution, then sodium thiosulfate solution. The combined aqueous extracts were washed with CH₂ Cl₂, and the combined organic extracts washed with saturated NaCl, dried (Na₂ SO₄) and concentrated giving 3.59 g crude material. The product was purified by flash chromatography on silica gel, eluting with petroleum ether with increasing amounts of CH₂ Cl₂ (0-40%), giving 3.05 g 2-amino-3-bromo-5-picoline, m.p. 68°-70° C.

To the above product (2.84 g, 15 mmol) in 50 mL CH₂ Cl₂ with 3.18 g (30 mmol) sodium carbonate, was added 2.07 g (18 mmol) thiophosgene. After stirring overnight at room temperature, the reaction was extracted with water, the aqueous phase back extracted with CH₂ C₂ and combined organic extracts washed with brine, dried (MgSO₄), and concentrated giving the isothiocyanate as an oily material that crystallized on standing (3.9 g) IR 2050 cm⁻¹.

To a solution of 1.0 g (4.3 mmol) of the isothiocyanate derivative and 1.04 g (4.3 mmol) of 2-cyclohexyl-1-phenylethylamine in 50 ml dry THF was added 438 mg (4.3 mmol) of Et₃ N. The resulting mixture was refluxed for two hours. The triethylamine hydrochloride was filtered off and the filtrate concentrated to give the thiourea (1.6 g) which crystallized on standing.

A mixture of 540 mg (1.15 mmol) of the thiourea and 317 mg (2.3 mmol) K2CO₃ in 10 mL DMF was refluxed overnight. The reaction mixture was then poured into water and extracted with ether(3X) and CH₂ Cl₂ (1X). The organic extracts were washed with brine, dried (Na₂ SO₄) and concentrated giving 450 mg product. Recrystallization from CH₂ Cl₂ /ether/petroleum ether gave 210 mg product, m.p. 213°-214° C.

Inhibition of LTB₄, biosynthesis in human polymorphonuclear leukocytes (PMNs)

The inhibition of leukotriene biosynthesis is measured by determining whether and to what extent test compounds can inhibit LTB₄ production from endogenous arachidonic acid in human peripheral blood leukocytes.

To 48-well tissue culture plates was added a solution of the test compound followed by addition of human polymorphonuclear leukocytes isolated from peripheral blood at a density of 1.5×10⁶ cells/well. Culture plates were preincubated for fifteen minutes with shaking at 28° C. Cells were stimulated with calcium ionophore A23187 at a final concentration of 2.5 μM for an additional ten minutes. The reaction was terminated by the addition of an EGTA solution (10 mM final concentration) followed by centrifugation at 1500 rpm at 10° C. Supernatants were stored at -70° C. LTB₄ levels were determined by RIA using a commercially available kit. Nonlinear regression analysis was used to calculate. IC₅₀ values.

The following tables show % inhibition of LTB₄ biosynthesis by compounds of the invention at test concentrations indicated, with the determined IC₅₀ shown in μM.

                  TABLE 1                                                          ______________________________________                                         Esters                                                                          ##STR7##                                                                      Comp                                        IC.sub.50                          No.   D/L.sup.a                                                                              R.sub.1 R.sub.3.sup.b                                                                          R.sub.16                                                                            X   mp   (μM)                            ______________________________________                                          1    DL      H       Ph4Cl   Et   S   Oil  0.2                                 2    DL      H       Ph4F    Et   S   129- 0.33                                                                      131                                      3    DL      H       Ph4Br   Et   S   104- 0.15                                                                      106                                      4    DL      H       Ph      Et   S   137- 0.4                                                                       139                                      5    L       H       Ph4OBZ  Et   S   Oil  0.53                                6    L       6-iPr   Ph      Et   S   Oil  0.25                                7    DL      6-iPr   Ph4Cl   Et   S   105- 0.33                                                                      107                                      8    L       6-iPr   Ph      Me   S   114- 0.14                                                                      115                                      9    DL      6-OMe   Ph4Cl   Et   S   129- 0.23                                                                      131                                     10    D       6-iPr   Ph      Me   S   115- 0.65                                                                      116                                     11    DL      6-nBu   Ph4Cl   Et   S   113- 0.17                                                                      114                                     12    L       6-Et    Ph      Et   S   102- 0.24                                                                      104                                     13    L       H       Ph      t-Bu S   50-  0.73                                                                      52                                      14    L       5-Et    Ph      Et   S   Oil  0.009                              15    L       5-Et    Cyh     Et   S   Oil  0.027                              16    L       H       Cyh     Et   S   resin                                                                               0.006                              17    L       H       Ph      Et   O   Oil  0.15                               18    D       H       Ph      Et   O   Oil  1.5                                19    L       5-iPr   Ph      Et   O   Oil  0.00052                            20    L       6-iPr   Ph      Et   O   Oil  0.22                               21    L       H       Cyh     Me   O   Oil  0.0064                             22    D       H       Cyh     Me   O   Oil  0.10                               23    L       5-iPr   Cyh     Me   O   Oil  0.001                              24    L       5-Me    Cyh     Me   O   Oil  0.0017                             25    L       5-Me    Cyh     t-Bu O   Oil  <0.3.sup.d                         26    D       5-Me    Cyh     Me   O   Oil  0.016                              27    DL      5-OMe   2Me4Thz Et   O   Oil  <0.3.sup.d                         28    DL      5-Cl    2-Thz   Et   O   Oil  <0.3.sup.d                         29    DL      5-Cl    2Me4Thz Et   O   Oil  0.087                              30    DL      5-iPr   3-Py    Et   O   Oil  0.19                               31    DL      5-iPr   4-Py    Et   O   Oil  <0.1.sup.d                         32    DL      5-OMe   3-Py    Et   O   Oil                                     33    DL      5-iPr   2Me4Thz Et   O   Oil  <0.03.sup.d                        ______________________________________                                          Footnotes (for TABLES 1 and 1A)                                                .sup.a DL = racemic. L or D indicates one enantiomer with stereochemistry      at chiral carbon analogous to the corresponding L or D amino acid.             .sup.b Ph = phenyl, PhX = substituted phenyl, Cyh = Cyclohexyl 2Thz =          2Thiazolyl, 2Me4Thz = 2methyl-4-thiazolyl, 3Py = 3pyridyl, 4Py = 4pyridyl      .sup.c One of a pair of diastereomers                                          .sup.d Greater than 504 inhibition at this concentration, IC.sub.50 not        characterized further.                                                   

                  TABLE 1A                                                         ______________________________________                                         Esters                                                                          ##STR8##                                                                      Comp                                           IC.sub.50                       No.   D/L     R.sub.6 R.sub.5                                                                              R.sub.3'                                                                             n   x   mp   (μM)                         ______________________________________                                         34    DL      H       H     CH.sub.3                                                                             0   S   Oil  1.4                             35    DL      H       H     CH.sub.3                                                                             0   S   Oil  0.68                            36    DL      CH.sub.3                                                                               H     H     0   S   Oil  1.0                             37    DL      H       H     H     1   S   69.5-                                                                               0.52                                                                      72                                   38    DL      H       CH.sub.3                                                                             H     0   S   97-  0.20                                                                      98                                   39    DL      H       CH.sub.3                                                                             H     0   O   89-  0.076                                                                     91.5                                 ______________________________________                                          Footnotes (for TABLES 1 and 1A)                                                .sup.a DL = racemic. L or D indicates one enantiomer with stereochemistry      at chiral carbon analogous to the corresponding L or D amino acid.             .sup.b Ph = phenyl, PhX = substituted phenyl, Cyh = Cyclohexyl 2Thz =          2Thiazolyl, 2Me4Thz = 2methyl-4-thiazolyl, 3Py = 3pyridyl, 4Py = 4pyridyl      .sup.c One of a pair of diastereomers                                          .sup.d Greater than 504 inhibition at this concentration, IC.sub.50 not        characterized further.                                                   

                  TABLE 2                                                          ______________________________________                                         Ester Bioisosteres - Amides                                                     ##STR9##                                                                      Comp                                           IC.sub.50                       No.    D/L    R.sub.1                                                                               R.sub.3.sup.a                                                                       R.sub.17                                                                            R.sub.18                                                                            x   m.p. °C.                                                                       (μM)                         ______________________________________                                         40     L      H      Ph   H    H    S   94-96  3                               41     DL     H      Ph   Me   Me   S   Oil    3                               42     DL     6-iPr  Ph   Et   H    S   161-163                                                                               3                               43     L      H      Ph   Me   OMe  O   Resin  <1.sup.c                        44     L      5-Me   Cyh  Me   H    O   202-204                                                                               0.072                           45     L      5-Me   Cyh  Me   OMe  O   Resin  0.03                            46     L      5-Me   Cyh  b    b    O   Resin  0.19                            ______________________________________                                          .sup.a See footnote b, Table 1.                                                .sup.b R.sub.17 and R.sub.18 with nitrogen make a piperidine ring.             .sup.c See footnote d, Tables 1 and 1A.                                  

                                      TABLE 3                                      __________________________________________________________________________     Ester Bioisosteres - Phenyl                                                     ##STR10##                                                                     Comp                        m.p.  IC.sub.50                                    No.  D/L.sup.a                                                                          R.sub.1                                                                               R.sub.3.sup.b                                                                        R.sub.4.sup.b                                                                      X °C.                                                                           (μM)                                      __________________________________________________________________________     47   DL  H      Ph    Ph  S 54-56 0.16                                         48   `L` H      Ph    Ph  S Oil   0.082                                        49   `D` H      Ph    Ph  S Oil   0.28                                         50   DL  H      Ph    Ph  O 154-156                                                                              <1.0.sup.d                                   51   DL  H      Cyh   Ph  O 129-131                                                                              0.0069                                       52   `D` H      Cyh   Ph  O 141-143                                                                              0.26                                         53   `L` H      Cyh   Ph  O 135.5-137                                                                            0.0036                                       54   DL  5-iPr  Cyh   Ph  O 119-122                                                                              0.0063                                       55   DL  H      Cyh   Ph4Cl                                                                              O 142-144                                                                              0.3                                          56   DL  H      Cyh   Ph4O                                                                               O 63-67 0.55                                                               Me                                                       57   DL  H      Cyh   Ph3Me                                                                              O 136-138                                                                              0.30                                         58   DL  H      Cyh   Ph2Cl                                                                              O 146-148                                                                              0.08                                         59   DL  5-I    Cyh   Ph  O 186-187                                                                              0.013                                        60   DL  5-NHSO.sub.2-                                                                         Cyh   Ph  O 188-190                                                                              0.16                                                  CH.sub.3                                                              61   DL  5-     Cyh   Ph  O 145-147                                                                              0.076                                                 NHC(O)CH.sub.3                                                        62   DL  5-NHC(O)                                                                              Cyh   Ph  O 211-212                                                                              <1.0.sup.d                                            NHCH.sub.3                                                            63   DL  5-CO.sub.2 H                                                                          Cyh   Ph  O 232-234                                                                              0.19                                         64   DL  5-C(O)NH.sub.2                                                                        Cyh   Ph  O 181-183                                                                              <1.0.sup.d                                   65   DL  5-C(O)N                                                                               Cyh   Ph  O 194-196                                                                              0.17                                                  Me.sub.2                                                              66   DL  6-CO.sub.2 H                                                                          Cyh   Ph  S 271-272                                                                              0.22                                         67   DL  5-CN   Cyh   Ph  O 166-168                                                                              0.15                                         68   DL  C      Cyh   Ph  O 154-156                                                                              <1.0.sup.d                                   69   DL  CH.sub.2 OH                                                                           Cyh   Ph  O 187-189                                                                              <1.0.sup.d                                   70   DL  5-tetra-                                                                              Cyh   Ph  O 188-191                                                                              0.16                                                  zolyl                                                                 71   DL  H      Cyh   Ph4F                                                                               O 144-145                                                                              0.17                                         72   L   5-Cl   NEt.sub.2                                                                            Ph  O 242-244                                                                              0.35                                         73   L   5-iPr  NnPr.sub.2                                                                           Ph  O Oil   <300.sup.d                                   74   L   5-iPr  OEt   Ph  O Oil   0.11                                         75   L   5-iPr  OnBu  Ph  O Oil   0.055                                        76   L   5-tBu  morph Ph  O 197-199                                                                              <0.03.sup.d                                  77   L   5-iPr  NEt.sub.2                                                                            Ph  O Oil   <0.3.sup.d                                   78   L   5-Cl   thiomorph                                                                            Ph  O 69-71 0.048                                        __________________________________________________________________________      .sup.a DL = racemic. `L` and `D` = L = isomer designation based on potenc      being greater than `D` isomer, and drawing analogy to esters where L and       are known.                                                                     .sup.b See footnote b, Table 1, also morph = Nmorpholinyl, thiomorph =         Nthiomorpholinyl.                                                              .sup.c morpholinecarbonyl                                                      .sup.d See Footnote d, Table 1.                                          

                                      TABLE 4                                      __________________________________________________________________________     Ester Bioisosteres - Pyridyl                                                    ##STR11##                                                                                          Pyridyl    IC.sub.50                                      79  D/L                                                                               X R.sub.1                                                                               R.sub.3.sup.a                                                                       Isomer                                                                              mp °C.                                                                        (μM)                                        __________________________________________________________________________     80  DL O H      Cyh  3    Resin 0.055                                          81  DL O 5-Me   Cyh  2    104-105                                                                              0.0031                                         82  DL O 5-Me   Cyh  3    150-151                                                                              0.024                                          83  DL O 5-Me   Cyh  4    188-189                                                                              0.19                                           84  DL O 6-NO.sub.2                                                                            Cyh  3      186-187.5                                                                          0.035                                          85  DL O 5-NO.sub.2                                                                            Cyh  3    189-190                                                                              0.024                                          86  DL O 5-Cl   Cyh  3    186-187                                                                              0.023                                          87  (-)*                                                                              O 5-Me   Cyh  2    Oil   0.0013                                         88  (+)*                                                                              O 5-Me   Cyh  2    Oil   0.045                                          89  (-)*                                                                              O 5-Me   Cyh  3    150-151                                                                              0.016                                          90  (+)*                                                                              O 5-Me   Cyh  3    150-151                                                                              <1.0                                           91  DL O 5-Cl   Cyh  2    132-134                                                                              0.002                                          92  DL O 5-CO.sub.2 Me                                                                         Cyh  2    129-131                                                                              0.012                                          93  DL O 5-Cl   Ph4F 2    112-114                                                                              0.019                                          94  DL O 5-iPr  Ph4F 2    56-58 0.012                                          95  DL O 5-CF.sub.3                                                                            Cyh  2    91-93 0.0012                                         96  DL S 5-Cl   Ph4F 2    133-135                                                                              0.027                                          97  DL S 5-Cl   Cyh  2    129-132                                                                              0.004                                          98  DL O 5-iPr  Ph4Cl                                                                               2    65-67 0.029                                          99  DL O 5-Cl   Ph4Cl                                                                               2    132-134                                                                              0.014                                          100 DL O 5-iPr  Ph3Cl                                                                               2    51-52 0.005                                          101 DL O 5-CO.sub.2 Me                                                                         Ph4F 2    151-152                                                                              0.027                                          102 DL S 5Cl    Cyh  2    129-132                                                                              0.004                                          103 DL O 5-SO.sub.2 NMe.sub.2                                                                  Ph4F 2    178-179                                                                              0.050                                          104 DL O 5-Cl   Ph4NO.sub.2                                                                         2    72-74 <0.03.sup.b                                    105 DL O 5-F    Ph3Cl                                                                               2    131-133                                                                              <0.03.sup.b                                    106 DL S 6-CF.sub.3                                                                            Ph4F 2    149-150                                                                              <1.0.sup.b                                     107 DL O 5-CF.sub.3                                                                            Ph4F 2    105-107                                                                              0.008                                          108 DL O 5-CF.sub.3                                                                            Cyh  2    91-93 0.001                                          109 DL O 5-F    Cyh  2      142-143.5                                                                          0.002                                          110 DL O 5-F    Ph4F 2      117-119.5                                                                          0.021                                          111 DL O 4,5-diF                                                                               Cyh  2    133-134                                                                              0.004                                          112 DL O 5,6-diF                                                                               Cyh  2    131-133                                                                              0.001                                          113 DL O 5,6-diF                                                                               Ph4F 2      143-144.5                                                                          0.024                                          114 DL O 5-OMe  Ph4F 2    111-113                                                                              0.011                                          115 DL O 5-NO.sub.2                                                                            Ph4F 2    174-175                                                                              <0.03.sup.b                                    116 DL O 5-iPr  2Me4Thz                                                                             2    116-117                                                                              <0.1.sup.b                                     117 DL O 5-Cl   2Me4Thz                                                                             2    142-143                                                                              <0.1.sup.b                                     118 (-)*                                                                              O 5-Cl   Ph4F 2    Oil   0.01                                           119 (+)*                                                                              O 5-Cl   Ph4F 2    Oil   0.32                                           __________________________________________________________________________      * (-) and (+) refer to the levorotatory and dextrorotatory enantiomer          respectively. Enantiomers were separated by HPLC on a Chiralcel OD column      eluting with hexane:iPrOH:Et.sub.2 NH 950:50:1.                                .sup.a See footnote b, Table 1.                                                .sup.b See footnote d, Table 1.                                          

                  TABLE 5                                                          ______________________________________                                         Ester Bioisosteres - Thiophene                                                  ##STR12##                                                                     Comp. No. D/L        mp °C.                                                                           IC.sub.50 (μM)                                ______________________________________                                         120       DL         108-110  0.0062                                           ______________________________________                                    

                  TABLE 6                                                          ______________________________________                                         Ester Bioisosteres - Methyloxadiazole                                          Comp. No.                                                                              D/L    R.sub.1                                                                               R.sub.3.sup.a                                                                         X   mp °C.                                                                          IC.sub.50 (μM)                     ______________________________________                                         121     DL     H      Ph     S   122-124 1.3                                   122     L      H      Ph     S   117-119 1.8                                   123     L      5-Et   Ph     S   134-136 <1.0.sup.b                            124     L      H      Cyh    S   147-149 0.12                                  125     L      5-Me   Cyh    O     118-119.5                                                                            0.028                                 126     DL     5-iPr  Ph4F   O   86      <0.3.sup.b                            127     DL     5-iPr  2Me4Thz                                                                               O   45-48   <1.0.sup.b                            ______________________________________                                          .sup.a See footnote b, Table 1.                                                .sup.b See footnote d, Table 1.                                          

                  TABLE 7                                                          ______________________________________                                         Ester Bioisosteres - Ketones                                                   Comp. No.                                                                              D/L    R.sub.1                                                                               R.sub.3.sup.a                                                                       R.sub.19                                                                            X   mp °C.                                                                         IC.sub.50 (μM)                   ______________________________________                                         128     L      6-iPr  Ph   CH.sub.3                                                                            S   107-110                                                                               0.35                                129     L      H      Ph   CH.sub.3                                                                            O   Oil    <1.0                                130     L      H      Ph   Ph   O   Resin  <0.3                                131     L      5-Me   Cyh  Ph   O   Resin  <1.0                                132     L      5-Me   Cyh  b    O   Resin  0.023                               ______________________________________                                          .sup.a See footnote b, Table 1.                                                b 1methyl-2-imidazolyl                                                   

                                      TABLE 8                                      __________________________________________________________________________     Ester Bioisosteres - Miscellaneous Acyclic                                      ##STR13##                                                                     Comp.                            IC.sub.50                                     No.  D/L                                                                               R.sub.1                                                                            R.sub.3.sup.a                                                                        R.sub.4   mp °C.                                                                       (μM)                                       __________________________________________________________________________     133  L  5-iPr                                                                              Ph    CH.sub.2 OEt                                                                             Oil  0.016                                         134  L  5-iPr                                                                              Ph    CH.sub.2 OPr                                                                             Oil  0.22                                          135  L  5-Cl                                                                               Ph    CH.sub.2 OEt                                                                             Oil  0.029                                         136  DL 5-iPr                                                                              Ph4F  CH.sub.2 OMe                                                                             Oil  <0.03.sup.b                                   137  DL 5-iPr                                                                              Ph4F  CH.sub.2 OEt                                                                             Oil  <0.03.sup.3                                   138  DL 5-iPr                                                                              Ph4F  CH.sub.2 OnPr                                                                            Oil  <0.3.sup.b                                    139  DL 5-iPr                                                                              Ph4OMe                                                                               CH.sub.2 OMe                                                                             Oil  <0.03.sup.b                                   140  DL 5-iPr                                                                              3-Py  CH.sub.2 OMe                                                                             Oil  <1.0.sup.b                                    141  DL 5-iPr                                                                              2Me4Thz                                                                              Ch.sub.2 OMe                                                                             Oil  <0.3.sup.b                                    142  L  5-iPr                                                                              Ph3Cl CH.sub.2 SMe                                                                             Oil  <0.03.sup.b                                   143  DL 5-iPr                                                                              3-Py  CH.sub.2 SMe                                                                             Oil  <1.0.sup.b                                    144  DL 5-iPr                                                                              4-Py  CH.sub.2 SMe                                                                             Oil                                                145  DL 5-iPr                                                                              2Me4Thz                                                                              CH.sub.2 SMe                                                                             Oil  <0.1.sup.b                                    146  DL 5-iPr                                                                              Ph    CH.sub.2 SO.sub.2 Me                                                                     resin                                                                               <0.03.sup.b                                   147  DL 5-iPr                                                                              3-Py  CH.sub.2 SO.sub.2 Me                                                                     88-92                                                                               <1.0.sup.b                                    148  DL 5-iPr                                                                              4-Py  CH.sub.2 SO.sub.2 Me                                                                     78-81                                              149  DL 5,6-diF                                                                            Ph4F  CH.sub.2 SO.sub.2 Me                                                                     179-181                                            150  L  5-iPr                                                                              Ph    CH.sub.2 NMe.sub.2                                                                       Oil  <0.3.sup.b                                    151  L  5-iPr                                                                              Ph    CH.sub.2 NHC(O)Me                                                                        resin                                                                               <0.1.sup.b                                    152  L  5-iPr                                                                              Ph    CH.sub.2 NHSO.sub.2 NMe.sub.2                                                            resin                                                                               <0.1.sup.b                                    153  L  5-iPr                                                                              Ph    CH.sub.2 NHC(O)NH.sub.2                                                                  resin                                                                               <0.3.sup.b                                    154  L  5-iPr                                                                              Ph    CH.sub.2 OC(O)NHMe                                                                       125-126                                                                             0.063                                         __________________________________________________________________________      .sup.a See footnote b, Table 1                                                 .sup.b See footnote d, Table 1                                           

                  TABLE 9                                                          ______________________________________                                         Ester Bioisosteres: Miscellaneous Heterocycle                                   ##STR14##                                                                     Comp.                                      IC.sub.50                           No.   D/L    R.sub.1                                                                               R.sub.3.sup.a                                                                          R.sub.4.sup.b                                                                          mp °C.                                                                         (μM)                             ______________________________________                                         155   DL     5-Cl   Ph4F    2-Imid  248-250                                                                               0.29                                156   DL     5-iPr  Ph4F    2-Imid  213-219                                                                               0.09                                157   DL     5-iPr  2-Me4Thz                                                                               2-Imid  153-155                                                                               <1.0.sup.c                          158   DL     5-iPr  Ph3Cl   2-Imid  210-213                                                                               <0.03.sup.c                         159   DL     5-iPr  Ph3Cl   2-Thz   resin  <0.1.sup.c                          160   DL     5-iPr  Ph3Cl   4Me2Thz resin  <0.03.sup.c                         161   DL     5-iPr  Ph      4-Pyraz 206-210                                                                               <0.1.sup.c                          ______________________________________                                          .sup.a See footnote b, Table 1.                                                .sup.b 2Imid = 2imidazolyl, 2Thz = 2thiazolyl, 4Me2Thz =                       4methyl-2-thiazolyl, 4Pyraz = 4pyrazolyl                                       .sup.c See footnote d, Table 1.                                          

                                      TABLE 10                                     __________________________________________________________________________     Oxazolopyridines                                                                ##STR15##                                                                     Comp.                            IC.sub.50                                     No.  D/L                                                                               X Y  R.sub.1                                                                            R.sub.3.sup.a                                                                       R.sub.4.sup.a                                                                       mp °C.                                                                        (μM)                                       __________________________________________________________________________     162  L  N C  H   Cyh  CO.sub.2 Me                                                                         147-149                                                                              0.21                                          163  DL N C  H   Cyh  Ph     189-190.5                                                                          0.078                                         164  DL N C  5-Me                                                                               Cyh  Ph   199-200                                                                              0.028                                         165  DL N C  5-Me                                                                               Cyh  2-Py 134-136                                                                              0.026                                         166  (-)*                                                                              N C  5-Me                                                                               Cyh  2-Py 68-75 0.015                                         167  (+)*                                                                              N C  5-Me                                                                               Cyh  2-Py 68-75 0.17                                          168  DL N C  5-Me                                                                               Cyh  3-Py 207-208                                                                              0.3                                           169  DL N C  S-Me                                                                               Ph4F 2-Py 66-69 <0.3.sup.b                                    170  DL C N  H   Cyh  Ph   133-134                                                                              0.021                                         171  DL C N  5-Me                                                                               Cyh  Ph   188-191                                                                              0.044                                         __________________________________________________________________________      .sup.a See footnote b Table 1. Also 2Py - 2pyridyl, 3Py = 3pyridyl.            .sup.b See footnote d, Table 1.                                                *See * Table 4.                                                          

                                      TABLE 11                                     __________________________________________________________________________     Thiazolopyridines                                                               ##STR16##                                                                     Comp.                            IC.sub.50                                     No.  D/L X  Y R.sub.1                                                                            R.sub.4.sup.a                                                                      R.sub.3.sup.a                                                                      mp °C.                                                                         (μM)                                       __________________________________________________________________________     172  DL  C  N H   Ph  Cyh 146-148                                                                               0.027                                         173  DL  C  N H   3-P Cyh .sup. 222-224.sup.a                                                                   0.17                                                            y                                                            174  DL  C  N H   2-Py                                                                               Cyh .sup. 176-178.sup.a                                                                   0.027                                         175  DL  C  N 5-Me-                                                                              2-Py                                                                               Cyh 215-217                                                                               0.009                                                       6-Br                                                             176  DL  C  N 5-Me                                                                               2-Py                                                                               Cyh 109-113                                                                               0.01                                          177  DL  C  N 5-Me                                                                               3-Py                                                                               Cyh   174-175.5                                                                           0.11                                          178  DL  C  N 6-Cl                                                                               3-Py                                                                               Cyh 207-209                                                                               0.044                                         179  DL  C  N 6-Cl                                                                               2-Py                                                                               Cyh 180-182                                                                               0.006                                         180  DL  C  N 4-Me                                                                               2-Py                                                                               Cyh 144-146                                                                               <1.0.sup.c                                    181  DL  C  N 6-Cl                                                                               3-Py                                                                               Cyh 207-209                                                                               0.044                                         182  DL  C  N 6-Cl                                                                               2-Py                                                                               Ph4F                                                                               151-153                                                                               0.110                                         183  DL  C  N 5-Cl                                                                               2-Py                                                                               Ph4F                                                                               146-149                                                                               0.280                                         184  DL  N  C 6-Me                                                                               2-Py                                                                               Cyh 214-216                                                                               0.031                                         185  DL  N  C 5-Me-                                                                              2-Py                                                                               Cyh 209-210                                                                               0.0065                                                      6-Br                                                             186  DL  N  C 5-Me-                                                                              3-Py                                                                               Cyh   241-243.5                                                                           0.021                                                       6-Br                                                             187  DL  N  C 5-Me                                                                               2-Py                                                                               Cyh 167-171                                                                               0.013                                         188  DL  N  C 6-Cl                                                                               2-Py                                                                               Cyh 198.5-200.5                                                                           0.0039                                        189  DL  N  C 6-Cl                                                                               2-Py                                                                               Ph4F                                                                               204-205                                                                               0.028                                         190  DL  C  N 5-Me-                                                                              3-Py                                                                               Cyh 211-212                                                                               <1.0.sup.c                                                  6-Br                                                             191  DL  N  C 6-Me                                                                               Ph  Cyh 213-214                                                                               <1.0.sup.c                                    192  DL  N  C 6-Me                                                                               2-Py                                                                               Ph4F                                                                               184-185                                                                               <0.3.sup.c                                    __________________________________________________________________________      .sup.a Hydrochloride salt.                                                     .sup.b See footnote b Table 1. Also 2Py = 2pyridyl, 3Py = 3pyridyl.            .sup.c See footnote d, Table 1.                                          

                  TABLE 12                                                         ______________________________________                                         Miscellaneous Compounds                                                         ##STR17##                                                                     Comp. No.                                                                              DL     R.sub.1                                                                               R.sub.4                                                                              X   mp °C.                                                                          IC.sub.50 (μM)                      ______________________________________                                         193     L      5-iPr  Ph.sup.b                                                                             C   165.sup.a                                                                              0.1                                    194     L      5-Me   Ph    C   >150.sup.a                                                                             0.23                                   195     L      5-iPr  2-Py  C   128.sup.                                                                               0.19                                   196     L      5-iPr  2-Py  O   135-137.5                                                                              <0.1.sup.c                             ______________________________________                                          .sup.a Dihydrochloride salt, broad melting range. (No. 143)                    .sup.b See footnote b, Table 1.                                                .sup.c See footnote d, Table 1.                                                .sup.d 2Py = 2pyridyl                                                    

                  TABLE 13                                                         ______________________________________                                         Miscellaneous Compounds                                                         ##STR18##                                                                     Comp. No.                                                                               DL     R.sub.1                                                                               R.sub.3.sup.a                                                                        mp °C.                                                                            IC.sub.50 (μM)                       ______________________________________                                         197      DL     5-Cl   2-Py  180-183.sup.                                                                            0.22                                     198      DL     5-iPr  2-Py  150-151.sup.b                                                                           0.12                                     199      DL     5-iPr  4-Py  145.sup.b                                                                               <0.3.sup.c                               200      DL     5-iPr  3-Py  resin    <0.3.sup.c                               ______________________________________                                          .sup.a 2-Py - 2pyridyl, 4Py = 4Pyridyl, 3Py = 3pyridyl                         .sup.b Tosylate salt                                                           .sup.c See footnote d, Table 1.                                          

                  TABLE 14                                                         ______________________________________                                         Miscellaneous Compounds                                                         ##STR19##                                                                     Comp.                                                                          No.   DL     R.sub.1                                                                               R.sub.4 R.sub.3                                                                              mp     IC.sub.50 (μM)                     ______________________________________                                         201   L      5-iPr  --CO.sub.2 Me                                                                          C     143-146.sup.a                                                                         <1.sup.b                              202   DL     5-iPr  d       Ph3Cl 168.5-170                                                                             <0.1.sup.b                            ______________________________________                                          .sup.a Hydrochloride Salt                                                      .sup.b See footnote d, Table 1.                                                .sup.c 1methyl-imidazol-4-yl                                                   .sup.d 1methyl-imidazol-2yl                                              

Antigen-Induced Bronchoconstriction in Guinea Pigs

This model measures the ability of a compound to block the leukotriene component of antigen-induced bronchoconstriction. Male Hartley guinea pigs are actively sensitized to ovalbumin, pretreated with mepyramine and indomethacin (to block the histamine and cyclooxygenase metabolite components respectively), and test compound (by aerosol administration). The guinea pigs are challenged with antigen (inhaled ovalbumin). Pulmonary function is measured by oscillatory mechanics as described by W. W. Wolyniec et al. (Agents and Actions 1991, 34, 1/2, 73). Results are expressed as percent inhibition of bronchoconstriction (resistance) in the test compound treated guinea pigs compared to placebo treated controls.

                  TABLE 15                                                         ______________________________________                                         Compound No.                                                                              Dose (Micrograms)*                                                                            N      % Inhibition                                  ______________________________________                                         51         274            6      86                                            56         95             6      43                                            81         308            6      64                                                       28             4      64                                                       2.8            10     61                                            165        274            7      84                                                       28             6      64                                                       5.6            4       0                                            ______________________________________                                          *Refers to amount of test compound inhaled by gunea pig. Compounds             administered by aerosolized freon/ethanol solution from metered dose           inhaler.                                                                  

What is claimed is:
 1. A compound having the following formula: ##STR20## wherein X is O or S;R₁ and R₂ are each, independent of one another, hydrogen; C₁ -C₆ alkyl; halo; CF₃ ; nitrile; C₁ -C₆ alkoxy; --CO₂ R₇ wherein R₇ is hydrogen or C₁ -C₆ alkyl; --C(O)NR₈ R₉ wherein R₈ and R₉ are hydrogen, C₁ -C₃ alkyl or methoxy; --NO₂ ; --NR₁₀ R₁₁ wherein R₁₀ and R₁₁ are hydrogen or C₁ -C₆ alkyl; --C(O)R₁₂ wherein R₁₂ is C₁ -C₆ alkyl; --SO₂ R₁₂ ; --NHC(O)R₁₂ ; --NHSO₂ R₁₂ ; or --SO₂ NR₁₃ R₁₄ wherein R₁₃ and R₁₄ are hydrogen or C₁ -C₆ alkyl; R₃ is cyclohexyl or an optionally substituted phenyl ring wherein the substituents are selected from halo, CF₃, C₁ -C₄ alkyl and C₁ -C₄ alkoxy; --S₂ R₁₂ ; NHC(O)R₁₂ ; --NHSO₂ -R₁₂ ; --SO₂ NR₁₃ R₁₄ or NO₂ ; or R₃ may be a pyrrolidine ring, an imidazole ring optionally substituted on nitrogen with C₁ -C₄ alkyl, a 2-thiazole ring or a 2-methyl-4-thiazole ring; R₃ may also be a dialkylamine (C₁ -C₄) or an alkyl ether (C₁ -C₄); R₄ is an ester --CO₂ R₁₆ wherein R₁₆ is C₁ -C₄ alkyl; or an amide of structure --C(O)NR₁₇ R₁₈ wherein R₁₇ and R₁₈ are hydrogen, C₁ -C₃ alkyl, or methoxy, or together with N form a pyrrolidine ring; an optionally substituted phenyl ring wherein the substituents are selected from halo, C₁ -C₄ alkyl and C₁ -C₄ alkoxy; a 3-methyl-1,2,4-oxadiazol-5-yl group; a 2- or 3-thienyl group; a 2-imidazole group optionally substituted on N with a methyl group; a 2-thiazole group optionally substituted on the 4-position with a methyl; a ketone C(O)R₁₉ wherein R₁₉ is C₁ -C₃ alkyl, phenyl or 1-methylimidazol-2-yl; an ether --CH₂ OR₂₀ where R₂₀ is C₁ -C₃ alkyl, a thioether, --CH₂ SR₂₀ ; a sulfone, --CH₂ SO₂ CH₃ ; an amine, --CH₂ N(R₂₀)₂ ; an amine derivative, --CH₂ NHC(O)R₂₁, where R₂₁ is CH₃ or NHCH₃, --CH₂ NHSO₂ Me₂ ; or a carbamate, --CH₂ OC(O)NHMe; R₅ and R₆ are independently of each other hydrogen or methyl; and n is an integer 0, 1 or 2, in racemic form, or the pure or substantially pure enantiomer thereof with the provisos that the following combination of substituents do not occur simultaneously: (i) R₁ or R₂ are hydrogen, halo, C₁ C₄ alkyl, C₁ -C₄ alkoxy, --CN, --NO₂ or --CF₃ ; R₃ is an unsubstituted phenyl; and R₄ is --C(O)OR₁₆. R₁₆ is alkyl, --C(O)NR₁₇ R₁₈ wherein R₁₇ and R₁₈ are hydrogen, methoxy, or together with N form a pyrrolidine ring; or (ii) R₄ is C(O)OCH₃, R₁ and R₂ are both hydrogen, and R₃ is unsubstituted phenyl or a 4-imidazole group.
 2. The compound as recited in claim 1 whereinR₁ and R₂ are C₁ --C₆ alkyl, halo, CF₃, C₁ -C₆ alkoxy or --SO₂ NR₁₃ R₁₄, wherein R₁₃ and R₁₄ are hydrogen or C₁ -C₆ alkyl; R₃ is cyclohexyl, an optionally substituted phenyl ring wherein the substituents are selected from halo, CF₃, C₁ -C₄ alkyl and C₁ -C₄ alkoxy, R₄ is an optionally substituted phenyl ring wherein the substituents are selected from halo, C₁ -C₄ alkyl and C₁ -C₄ alkoxy, a 3-methyl-1,2,4-oxadiaxol-5-yl group; and a 2-thienyl group; and n is 1 or
 2. 3. The compound as recited in claim 1 wherein R₁ is in the 5-position and is C₁ -C₃ alkyl or halo,R₂ is hydrogen, R₃ is cyclohexyl, R₄ is phenyl, R₅ is hydrogen, R₆ is hydrogen, X is O or S, and n is
 1. 4. The compound as recited in claim 1 ##STR21## wherein R₁ is hydrogen,R₃ is cyclohexyl and R₄ is phenyl.
 5. A pharmaceutical composition of matter comprising a compound having the following formula ##STR22## wherein X is O or S;R₁ and R₂ are each, independent of one another, hydrogen; C₁ -C₆ alkyl; halo; CF₃ ; nitrile; C₁ -C₆ alkoxy; --CO₂ R₇ wherein R₇ is hydrogen or C₁ -C₆ alkyl; --C(O)NR₈ R₉ wherein R₈ and R₉ are hydrogen, C₁ -C₃ alkyl or methoxy, --NO₂ ; --NR₁₀ R₁₁ wherein R₁₀ and R₁₁ are hydrogen or C₁ -C₆ alkyl; --C(O)R₁₂ wherein R₁₂ is C₁ -C₆ alkyl; --SO₂ R₁₂ ; --NHC(O)R₁₂ ; --NHSO₂ R₁₂ ; or SO₂ NR₁₃ R₁₄ wherein R₁₃ and R₁₄ are hydrogen or C₁ -C₆ alkyl; R₃ is cyclohexyl or an optionally substituted phenyl ring wherein the substituents are selected from halo, CF₃, C₁ -C₄ alkyl and C₁ -C₄ alkoxy; --SO₂ R₁₂ ; NHC(O)R₁₂ ; --NHSO₂ R₁₂ ; --SO₂ NR₁₃ R₁₄ or NO₂ ; or R₃ may be a pyrrolidine ring, or an imidazole ring optionally substituted on nitrogen with C₁ -C₄ alkyl, a 2-thiazole ring or a 2-methyl-4-thiazole ring; R₃ may also be a dialkylamine (C₁ -C₄) or an alkyl ether (C₁ -C₄); R₄ is an ester--CO₂ R₁₆ wherein R₁₆ is C₁ -C₄ alkyl; or an amide of structure --C(O)NR₁₇ R₁₈ wherein R₁₇ and R₁₈ are hydrogen, C₁ -C₃ alkyl, methoxy, or together with N form a pyrrolidine ring; an optionally substituted phenyl ring wherein the substituents are selected from halo, C₁ -C₄ alkyl and C₁ -C₄ alkoxy; a 3-methyl-1,2,4-oxadiazol-5-yl group; a 2- or 3-thienyl group; a 2-thiazole group optionally substituted on the 4-position with a methyl; a ketone C(O)R₁₉ wherein R₁₉ is C₁ -C₃ alkyl, phenyl or 1-methylimidazol-2-yl; an ether --CH₂ OR₂₀ where R₂₀ is C₁ -C₃ alkyl, a thioether, --CH₂ SR₂₀ ; a sulfone, --CH₂ SO₂ CH₃ ; an amine, --CH₂ N(R₂₀)₂ ; an amine derivative, --CH₂ NHC(O)R₂₁ wherein R₂₁ is CH₃ or NHCH₃, --CH₂ NHSO₂ Me₂ ; or a carbamate, --CH₂ OC(O)NHMe; R₅ and R₆ are independently or each other hydrogen or methyl; and n is an integer 0, 1 or 2, in racemic form, or the pure or substantially pure enantiomer thereof.
 6. A method of treating disease in a warm-blooded animal through inhibition of leukotriene biosynthesis which comprises administering to the animal a leukotriene biosynthesis inhibiting amount of a compound having the following formula: ##STR23## wherein X is O or S;R₁ and R₂ are each, independent of one another, hydrogen; C₁ -C₆ alkyl; halo; CF₃ ; nitrile; C₁ -C₆ alkoxy; --CO₂ R₇ wherein R₇ is hydrogen or C₁ -C₆ alkyl; --C(O)NR₈ R₉ wherein R₈ and R₉ are hydrogen, C₁ -C₃ alkyl or methoxy; --NO₂ ; --NR₁₀ R₁₁ wherein R₁₀ and R₁₁ are hydrogen or C₁ -C₆ alkyl; --C(O)R₁₂ wherein R₁₂ is C₁ -C₆ alkyl; --SO₂ R₁₂ ; --NHC(O)R₁₂ ; --NHSO₂ R₁₂ ; or --SO₂ NR₁₃ R₁₄ wherein R₁₃ and R₁₄ are hydrogen or C₁ -C₆ alkyl; R₃ is cyclohexyl or an optionally substituted phenyl ring wherein the substituents are selected form halo, CF₃, C₁ -C₄ alkyl and C₁ -C₄ alkoxy; --SO₂ R₁₂ ; NHC(O)R₁₂ ; --NHSO₂ -R₁₂ ; --SO₂ NR₁₃ R₁₄ or NO₂ ; or R₃ may be a pyrrolidine ring, an imidazole ring optionally substituted on nitrogen with C₁ -C₄ alkyl, a 2-thiazole ring or a 2-methyl-4-thiazole ring; R₃ may also be a dialkylamine (C₁ -C₄) or an alkyl ether (C₁ -C₄); R₄ is an ester --CO₂ R₁₆ wherein R₁₆ is C₁ -C₄ alkyl; or an amide of structure --C(O)NR₁₇ R₁₈ wherein R₁₇ and R₁₈ are hydrogen, C₁ -C₃ alkyl or methoxy; an optionally substituted phenyl ring wherein the substituents are selected from halo, C₁ -C₄ alkyl and C₁ -C₄ alkoxy; a 3-methyl-1,2,4-oxadiazol-5-yl group; a 2- or 3-thienyl group; a 2-imidazole group optionally substituted on the 4-position with a methyl; a ketone C(O)R₁₉ wherein R₁₉ is C₁ -C₃ alkyl, phenyl or 1-methylimidazol-2-yl; an ether --CH₂ OR₂₀ where R₂₀ is C₁ -C₃ alkyl, a thioether,--CH₂ SR₂₀ ; a sulfone, --CH₂ SO₂ CH₃ ; an amine, --CH₂ N(R₂₀)₂ ; an amine derivative, --CH₂ NHC(O)R₂₁, where R₂₁ is CH₃ or NHCH₃, --CH₂ NHSO₂ Me₂ ; or a carbomate, --CH₂ OC(O)NHMe; R₅ and R₆ are independently of each other hydrogen or methyl and n is an integer 0, 1 or 2, in racemic form, or the pure or substantially pure enantiomer. 